5,6-dihydro-dibenz[b,e]azepine-6,11-dione-11-oximes

ABSTRACT

The invention relates to 5,6-dihydro-dibenz[b,e]azepine-6,11-dione-11-oximes, to processes for their preparation and to their use as inhibitors of reverse transcriptase and in particular as antiretroviral agents.

The invention relates to5,6-dihydro-dibenz[b,e]azepine-6,11-dione-11-oximes and to processes fortheir preparation.

DE 1,545,856 discloses a process for the preparation of basicallysubstituted derivatives of5,6-dihydrodibenz[b,e]azepine-6,11-dione-11-oxime, a few examples withaminoalkyl radicals on the oxime oxygen also being described therein.

In addition, U.S. Pat. No. 3,431,257 discloses some basicallysubstituted 5,6-dihydro-dibenz[b,e]azepine-6,11-dione-11-oximes withpsychotropic action, the compounds of the general formula (I) accordingto the invention partially being covered by the wording of the scope ofmeaning (R¹ =alkyl) of these publications.

The present invention relates to5,6-dihydrodibenz[b,e]azepine-6,11-dione-11-oximes of the generalformula (I) ##STR1## in which A, B and D are identical or different andrepresent hydrogen, amino, nitro, halogen, cyano, hydroxyl,trifluoromethyl, trifluoromethoxy or straight-chain or branched alkyl oralkoxy each having up to 8 carbon atoms,

E represents hydrogen or straight-chain or branched alkyl having up to 6carbon atoms,

R¹ represents hydrogen or represents cycloalkyl having 3 to 6 carbonatoms or 2-tetrahydropyranyl, represents straight-chain or branched acylhaving up to 8 carbon atoms, or represents straight-chain or branchedalkyl or alkenyl each having up to 10 carbon atoms, each of which isoptionally substituted by halogen, hydroxyl or carboxyl, bystraight-chain or branched alkoxycarbonyl having up to 6 carbon atoms orby phenyl which in turn can be substituted up to 5 times by identical ordifferent halogen,

if appropriate in an isomeric form, and their physiologically acceptablesalts.

Physiologically acceptable salts of the5,6-dihydrodibenz[b,e]azepine-6,11-dione-11-oximes can be salts of thesubstances according to the invention with mineral acids, carboxylicacids or sulphonic acids. Particularly preferred salts are, for example,those with hydrochloric acid, hydrobromic acid, sulphuric acid,phosphoric acid, methanesulphonic acid, ethanesulphonic acid,toluenesulphonic acid, benzenesulphonic acid, naphthalenedisulphonicacid, acetic acid, propionic acid, lactic acid, tartaric acid, citricacid, fumaric acid, maleic acid or benzoic acid.

The compounds according to the invention can exist in stereoisomericforms, which either behave as image and mirror image (enantiomers), orwhich do not behave as image and mirror image (diastereomers). Theinvention relates both to the antipodes and to the racemic forms as wellas to the diastereomer mixtures. The racemic forms can be separated,like the diastereomers, into the stereoisomerically uniform constituentsin a known manner [cf. E. L. Eliel, Stereochemistry of Carbon Compounds,McGraw Hill, 1962].

In the radical of the general formula (II) ##STR2## the C═N double bondcan have either the E- or the Z-configuration, or E/Z mixtures can bepresent.

Preferred compounds of the general formula (I) are those in which

A, B and D are identical or different and represent hydrogen, fluorine,chlorine, hydroxyl, trifluoromethyl, trifluoromethoxy or straight-chainor branched alkyl or alkoxy each having up to 6 carbon atoms,

E represents hydrogen or straight-chain or branched alkyl having up to 4carbon atoms,

R¹ represents hydrogen or represents cyclopropyl, cyclopentyl,cyclohexyl or 2-tetrahydropyranyl, or represents straight-chain orbranched acyl having up to 6 carbon atoms, or represents straight-chainor branched alkyl or alkenyl each having up to 8 carbon atoms, each ofwhich can optionally be substituted by fluorine, hydroxyl or carboxyl,by straight-chain or branched alkoxycarbonyl having up to 4 carbon atomsor by phenyl which in turn can be substituted up to 5 times by identicalor different fluorine, chlorine or bromine,

if appropriate in an isomeric form, and their physiologically acceptablesalts.

Particularly preferred compounds of the general formula (I) are those

in which

A, B and D are identical or different and represent hydrogen, fluorine,chlorine or straight-chain or branched alkyl or alkoxy each having up to4 carbon atoms,

E represents hydrogen, methyl or ethyl,

R¹ represents hydrogen or represents cyclopropyl or 2-tetrahydropyranyl,or represents straight-chain or branched acyl having up to 4 carbonatoms, or represents straight-chain or branched alkyl or alkenyl eachhaving up to 6 carbon atoms, each of which is optionally substituted byhydroxyl, carboxyl, fluorine, methoxycarbonyl, ethoxycarbonyl orpropoxycarbonyl or by phenyl which in turn can be substituted up to 5times by identical or different fluorine or chlorine,

if appropriate in an isomeric form, and their physiologically acceptablesalts.

The compounds of the general formula (I) according to the invention canbe prepared by a process in which

[A] compounds of the general formula (III) ##STR3## in which A, B, D andE have the abovementioned meaning,

are reacted with hydroxylamines of the general formula (IV)

    H.sub.2 N--OR.sup.1                                        (IV)

in which

R¹ has the abovementioned meaning,

in inert solvents, if appropriate in the presence of a base,

or

[B]compounds of the general formula (Ia) ##STR4## in which A, B, D and Ehave the abovementioned meaning,

are reacted with compounds of the general formula (V)

    L--R.sup.2                                                 (V)

in which

R² has the abovementioned meaning of R¹ but does not represent hydrogen,

and

L represents a typical leaving group, such as, for example, tosylate,mesylate, chlorine, bromine or iodine,

likewise in inert solvents in the presence of a base, and, ifappropriate, the substituents A, B, D and R¹ are varied according tocustomary chemical methods,

and in the case in which E does not denote hydrogen, an alkylation islikewise carried out according to known methods.

The processes according to the invention can be illustrated by way ofexample by the following reaction scheme: ##STR5##

The abovementioned processes are carried out in analogy to the methodsdescribed in U.S. Pat. No. 3,431,257.

Suitable solvents for processes [A] and [B] are the customary organicsolvents which do not change under the reaction conditions. Thesepreferably include ethers such as diethyl ether, dioxane,tetrahydrofuran, glycol dimethyl ether, or hydrocarbons such as benzene,toluene, xylene, hexane, cyclohexane or mineral oil fractions, orhalogenohydrocarbons such as dichloromethane, trichloromethane,tetrachloromethane, dichloroethylene, trichloroethylene orchlorobenzene, or ethyl acetate, or triethylamine, pyridine, dimethylsulphoxide, dimethylformamide, hexamethylphosphoric triamide,acetonitrile, acetone or nitromethane. It is also possible to usemixtures of the solvents mentioned. Pyridine and tetrahydrofuran arepreferred.

Suitable bases are the customary basic compounds. These preferablyinclude alkali metal or alkaline earth metal hydroxides, such as lithiumhydroxide, sodium hydroxide, potassium hydroxide or barium hydroxide,alkali metal hydrides such as sodium hydride, alkali metal or alkalineearth metal carbonates such as sodium carbonate or potassium carbonate,or alkali metal alkoxides such as, for example, sodium methoxide orethoxide, potassium methoxide or ethoxide or potassium tert-butoxide, ororganic amines such as benzyltrimethylammoniumhydroxide,tetrabutylammonium hydroxide, pyridine, triethylamine orN-methylpiperidine.

Processes [A] and [B] are in general carried out in a temperature rangefrom +0° C. to +150° C., preferably from 0° C. to +120° C.

The process is in general carried out at normal pressure. However, it isalso possible to carry out the process at reduced pressure or atelevated pressure (for example in a range from 0.5 to 5 bar).

Suitable solvents for the alkylation (E≠H) are likewise customaryorganic solvents which do not change under the reaction conditions.These preferably include ethers such as diethyl ether, dioxane,tetrahydrofuran, glycol dimethyl ether, or hydrocarbons such as benzene,toluene, xylene, hexane, cyclohexane or mineral oil fractions, orhalogenohydrocarbons such as dichloromethane, trichloromethane,tetrachloromethane, dichloroethylene, trichloroethylene orchlorobenzene, or ethyl acetate, or triethylamine, pyridine, dimethylsulphoxide, dimethylformamide, hexamethylphosphoric triamide,acetonitrile, acetone or nitromethane. It is also possible to usemixtures of the solvents mentioned. Acetone is preferred.

The alkylation is carried out in the abovementioned solvents attemperatures of 0° C. to +150° C., preferably at room temperatures up to+100° C., at normal pressure.

The compounds of the general formula (III) are known per se or can beprepared according to customary methods [cf., for example, U.S. Pat. No.3,431,257].

The hydroxylamines of the general formula (IV) are also known or can beprepared according to known methods.

The compounds of the general formula (Ia), in the case in whichE≠hydrogen, are covered by the scope of meaning of U.S. Pat. No.3,431,257 or are new and can then be prepared by the process [A]described above.

The compounds of the general formula (V) are known [cf. Beilstein1,114].

The inhibitors described herein are inhibitors of reverse transcriptaseand can be employed as such for all purposes for which enzyme inhibitorsare suitable. This is, for example, use in diagnosis in order to improvethe precision and selectivity of enzyme activity measurements. Inaffinity chromatography, they can be used as an affinity label and inresearch they can be used for the elucidation of reaction mechanisms ofenzymatic reactions.

Moreover, it has surprisingly been found that the compounds of thegeneral formula (I) according to the invention have an extremely strongaction against retroviruses. They show activity in lentivirus-infectedcell cultures. It was possible to show this by way of the HIV virus.

HIV infection in cell culture

The HIV test was carried out with slight modifications according to themethod of Pauwels et al. [cf. Journal of Virological Methods 20, (1988),309-321].

Normal human blood lymphocytes (PBLs) were concentrated by means ofFicoll-Hypaque and stimulated with phytohaemagglutinin (90 μg/ml) andinterleukin-2 (40 U/ml) in RPMI 1640 and 20% foetal calf serum. Forinfection with the infectious HIV, PBLs were pelleted and the cellpellet was then suspended in 1 ml of HIV virus adsorption solution andincubated for 1 hour at 37° C.

Alternatively, HIV-susceptible H9 cells were employed instead of normalhuman blood lymphocytes for testing the antiviral effects of thecompounds according to the invention.

The virus adsorption solution was centrifuged and the infected cellpellet was taken up in growth medium so that a concentration of 1×10⁵cells per ml was established. The cells infected in this way werepipetted into the wells of 96-well microtiter plates to give 1×10⁴cells/well.

The first vertical row of the microtiter plate contained only growthmedium and cells which had not been infected, but otherwise treatedexactly as described above (cell control). The second vertical row ofthe microtiter plate contained only HIV-infected cells (virus control)in growth medium. The other wells contained the compounds according tothe invention in differing concentrations, starting from the wells ofthe 3rd vertical row of the microtiter plate, from which the testsubstances were diluted 2¹⁰ times in 2-fold steps.

The test batches were incubated at 37° C. until, in the untreated viruscontrol, the syncytia formation typical of HIV occurred (between day 3and 6 after infection), which was then microscopically assessed. Underthese test conditions, in the untreated virus control about 20-50syncytia resulted, while the untreated cell control contained nosyncytia.

The IC₅₀ values were determined as the concentration of the treated andinfected cells at which 50% (about 10-20 syncytia) of the virus-inducedsyncytia were suppressed by treatment with the compound according to theinvention.

It has now been found that the compounds according to the inventionprotect HIV-infected cells from virus-induced cell destruction.

                  TABLE 1:                                                        ______________________________________                                        Ex. No.        IC.sub.50 (μM)                                              ______________________________________                                        4              0.06                                                           6              1.5                                                            8              0.5                                                            17             0.7                                                            18             1.0                                                            24             2.3                                                            31             0.25                                                           (comparison)   0.09                                                           BIRG 587                                                                      [J.Med.                                                                       Chem. 34                                                                      2231, (1991]                                                                  ______________________________________                                    

The compounds according to the invention are useful active substances inhuman and veterinary medicine for the treatment and prophylaxis ofdiseases caused by retroviruses.

Indication areas in human medicine which can be mentioned are, forexample:

1.) The treatment and prophylaxis of human retrovirus infections.

2.) For the treatment or prophylaxis of diseases (AIDS) caused by HIV I(human immunodeficiency virus; formally called HTLV III/LAV) and HIV IIand the stages associated therewith such as ARC (AIDS-related complex)and LAS (lymphadenopathy syndrome) and also the immunodeficiency andencephalopathy caused by this virus.

3.) For the treatment or the prophylaxis of an HTLV-I or HTLV-IIinfection.

4.) For the treatment or the prophylaxis of the AIDS-carrier state(AIDS-transmitter state).

Indications in veterinary medicine which can be mentioned are, forexample:

Infections with

a) Maedivisna (in sheep and goats)

b) progressive pneumonia virus (PPV) (in sheep and goats)

c) caprine arthritis encephalitis virus (in sheep and goats)

d) Zwoegerziekte virus (in sheep)

e) infectious anaemia virus (of the horse)

f) infections caused by feline leukaemia virus

g) infections caused by feline immunodeficiency virus (FIV)

h) infections caused by simian immunodeficiency virus (SIV)

The abovementioned items 2, 3 and 4 are preferred from the indicationarea in human medicine.

The present invention includes pharmaceutical preparations which, inaddition to non-toxic, inert pharmaceutically suitable excipients,contain one or more compounds of the formula (I) or which consist of oneor more active substances of the formula (I), and processes for theproduction of these preparations.

The active substances of the formula (I) should preferably be present inthe abovementioned pharmaceutical preparations in a concentration ofabout 0.1 to 99.5% by weight, preferably of about 0.5 to 95% by weight,of the total mixture.

Apart from the compounds of the formula (I), the abovementionedpharmaceutical preparations can also contain other pharmaceutical activesubstances.

The abovementioned pharmaceutical preparations are prepared in acustomary manner by known methods, for example by mixing the activesubstance or substances with the excipient or excipients.

In general, it has proved advantageous both in human and in veterinarymedicine to administer the active substance or substances according tothe invention in total amounts of about 0.1 to about 200 mg/kg,preferably 1 to 100 mg/kg, of body weight every 24 hours, if appropriatein the form of several individual doses, to achieve the desired results.An individual dose contains the active substance or substancespreferably in amounts of about 1 to about 80, in particular 1 to 30,mg/kg of body weight. However, it may be necessary to depart from thedosages mentioned, in particular depending on the nature and the bodyweight of the subject to be treated, the type and the severity of thedisease, the type of preparation and the administration of themedicament as well as the time or interval within which administrationtakes place.

PREPARATION EXAMPLES Example 1(E/Z)-2-Chloro-11-hydroxyimino-6-oxo-5,6-dihydro-11-H-dibenz[b,e]azepine##STR6##

10 g (39 mmol) of 2-chloro-6,11-dioxo-5,6-dihydro-11H-dibenz[b,e]azepineand 3.24 g (46 mmol) of hydroxylamine hydrochloride in 80 ml of pyridineare heated at 100° C. for 18 h. The mixture is then poured into 2Nhydrochloric acid and the precipitated product is filtered off.Recrystallisation from ethanol yields 9.23 g of the oxime.

Example 2(E/Z)-11-tert-Butoxyimino-2-chloro-6-oxo-5,6-dihydro-11-H-dibenz[b,e]azepine ##STR7##

0.5 g (2.2 mmol) of2-chloro-6,11-dioxo-5,6-dihydro-11-H-dibenz[b,e]azepine and 304 mg (2.4mmol) of 0-tert-butylhydroxylamine in 4.4 ml of pyridine are heated at100° C. for 6 h. The mixture is then poured into 2 N hydrochloric acidand the precipitated product is filtered off. Recrystallisation fromethanol/water yields 307 mg of product.

¹ H-NMR (DMSO): δ=1.30 and 1.31 (2s, 9H); 7.20 and 7.25 (2d, J=9 Hz,1H); 7.35-7.8 (m, 5H); 7.9 (m, 1H); 10.68 and 10.74 (2s, NH).

Example 3(E/Z)-2-Chloro-11-isopropoxymino-6-oxo-5,6-dihydro-11-H-dibenz[b,e]azepine##STR8##

300 mg (1.1 mmol) of(E/Z)-2-chloro-11-hydroxyimino-6-oxo-5,6-dihydro-11H-dibenz[b,e]azepinein 2.2 ml of abs. THF are treated with 36.3 mg (1.2 mmol) of an 80%strength suspension of NaH in oil and heated under reflux for 30 min.121 μl (1.21 mmol) of 2-iodopropane are added and the mixture is heatedunder reflux for a further 18 h. It is then filtered, the filtrate isconcentrated and the residue is purified on silica gel using CH₂ Cl₂/EtOAc 10:1.

Yield: 125 mg

¹ H-NMR (CDCl₃): δ=1.23 and 1.28 (2d, J=6 Hz, 3H); 1.32 and 1.36 (2d,J=6 Hz, 3H); 4.50 and 4.52 (2 septet, J=6 Hz, 1H); 7.05 and 7.10 (2d,J=9 Hz, 1H); 7.28 (m, 1H); 7.48-7.65 (m, 4H); 8.08 (d, J=9 Hz, 1H); 9.08and 9.12 (2s, NH).

Example 4 (E) -2-Chloro-11-ethoxyimino-6-oxo-5,6-dihydro-11-H-dibenz[b,e]azepine ##STR9##

(E/Z)-2-Chloro-11-hydroxyimino-6-oxo-5,6-dihydro-11-H-dibenz[b,e]azepineis separated into the pure (E) and (Z) components by HPLC on an Si60phase and 3% isopropanol in petroleum ether. 50 mg (0.18mmol) of the (E)compound in 0.18 ml of ethanol and 0.54 ml of THF are treated at 0° C.with 71 mg (0.27 mmol) of triphenylphosphane and then with a solution of56 μl (0.36 mmol) of diethyl azodicarboxylate in 0.18 ml of ethanol. Themixture is stirred overnight at room temperature and evaporated and theresidue is purified on silica gel using CH₂ Cl₂ /EtOAc 30:1.

Yield: 29 mg

¹ H-NMR (CDCl₃): δ=1.30 (t, J=6 Hz, 3H); 4.26 (m, 2H); 7.00 (d, J=8 Hz,1H); 7.30 (m, 1H); 7.45-7.70 (m, 4H); 8.08 (d, J=8 Hz, 1H); 8.61 (s,NH).

The examples shown in Table 1 are prepared in analogy to the proceduresof Examples 1-4:

                                      TABLE 1                                     __________________________________________________________________________     ##STR10##                                                                                                               analogous                          Ex. No.                                                                             A    B    D    E    R.sup.1      E/Z to Example                         __________________________________________________________________________     5    H    H    H    H    CH.sub.3     1:1 2                                   6    H    H    Cl   H    CH.sub.3     1:1 2                                   7    H    H    Cl   CH.sub.3                                                                           CH.sub.3     1:1 2                                   8    H    H    Cl   H    C.sub.2 H.sub.5                                                                            Z   4                                   9    H    H    H    H    C.sub.2 H.sub.5                                                                            1:1 2                                  10    Cl   H    H    H    C.sub.2 H.sub.5                                                                            1:1 2                                  11    CH.sub.3                                                                           H    H    H    C.sub.2 H.sub.5                                                                            1:1 2                                  12    H    CH.sub.3                                                                           H    H    C.sub.2 H.sub.5                                                                            1:1 2                                  13    H    H    CH.sub.3                                                                           H    C.sub.2 H.sub.5                                                                            1:1 2                                  14    H    H    Cl   H    C.sub.3 H.sub.7                                                                            1:1 3                                  15    H    H    Cl   H                                                                                   ##STR11##   1:1 2                                  16    H    H    Cl   H    CH.sub.2CHCH.sub.2                                                                         1:1 2                                  17    H    H    Cl   H    CH.sub.2 C.sub.6 H.sub.5                                                                   1:1 2                                  18    H    H    Cl   H                                                                                   ##STR12##   1:1 2                                  19    H    H    Cl   H                                                                                   ##STR13##   1:1 2                                  20    H    H    H    H    CH.sub.2 CO.sub.2 H                                                                        1:1 2                                  21    H    H    Cl   H    CH.sub.2 CO.sub.2 H                                                                        1:1 2                                  22    H    H    H    H    CH.sub.2 CO.sub.2 CH.sub.3                                                                 1:1 2                                  23    H    H    H    H    CH.sub.2 CO.sub.2 CH.sub.3                                                                 Z   4                                  24    H    H    Cl   H    CH.sub.2 CO.sub.2 CH.sub.3                                                                 1:1 2                                  25    H    H    Cl   H    CH.sub.2 CO.sub.2 CH.sub.3                                                                 Z   4                                  26    H    H    Cl   CH.sub.3                                                                           CH.sub.2 CO.sub.2 CH.sub.3                                                                 1:1 2                                  27    H    H    H    H    CH.sub.2 CO.sub.2 C.sub.2 H.sub.5                                                          1:1 2                                  28    H    H    Cl   H    CH.sub.2CO.sub.2 C.sub.2 H.sub.5                                                           1:1 2                                  29    H    H    Cl   CH.sub.3                                                                           CH.sub.2CO.sub.2 C.sub.2 H.sub.5                                                           1:1 2                                  30    H    H    Cl   H    (CH.sub.2).sub.4 CO.sub.2 C.sub.2 H.sub.5                                                  1:1 2                                  31    H    H    Cl   H                                                                                   ##STR14##   1:1 2                                  32    H    H    Cl   H    (CH.sub.2).sub.2 OH                                                                        1:1 2                                  33    H    H    Cl   H    COCH.sub.3   1:1 2                                  34    H    H    Cl   H                                                                                   ##STR15##   Z   4                                  35    H    H    Cl   H                                                                                   ##STR16##   E   4                                  __________________________________________________________________________

We claim:
 1. 5,6-Dihydro-dibenz[b ,e]azepine-6,11-dione-11-oximes of theformula (I): ##STR17## in which A, B and D are indentical or differentand represent hydrogen, amino, nitro, halogen, cyano, hydroxyl,trifluoromethyl, trifluoromethoxy or straight-chain or branched alkyl oralkoxy each having up to 8 carbon atoms;E represents hydrogen orstaight-chain or branched alkyl having up to 6 carbon atoms; and R¹represents cycloalkyl having 3 to 6 carbon atoms; orrepresents2-tetrahydropyranyl; or represents straight-chain or branched acylhaving up to 8 carbon atoms; or represents straight-chain or branchedalkyl having up to 10 carbon atoms which is substituted by halogen,hydroxyl, carboxyl, straight-chain or branched alkoxycarbonyl having upto 6 carbon atoms, or by phenyl which is optionally substituted up to 5times by identical or different halogen atoms; or representsstraight-chain or branched alkenyl having up to 10 carbon atoms which isoptionally substituted by halogen, hydroxyl, carboxyl, straight-chain orbranched alkoxycarbonyl having up to 6 carbon atoms, or by phenyl whichis optionally substituted up to 5 times by identical or differenthalogen atoms;if appropriate in an isomeric form, or a physiologicallyacceptable salt thereof.
 2. A compound according to claim 1, whereinsuch compound is selected from the group consisting of: ##STR18## 3.5,6-Dihydro-dibenz[b,e]azepine-6,11-dione-11-oximes of the formula (I):##STR19## in which A, B and D are indentical or different and representamino, nitro, cyano, hydroxyl, trifluoromethyl or trifluoromethoxy;Erepresents hydrogen or staight-chain or branched alkyl having up to 6carbon atoms; and R¹ represents hydrogen; orrepresents cycloalkyl having3 to 6 carbon atoms; or represents 2-tetrahydropyranyl; or representsstraight-chain or branched acyl having up to 8 carbon atoms; orrepresents straight chain or branched alkyl having up to 10 carbon atomswhich is optionally substituted by halogen, hydroxyl, carboxyl,straight-chain or branched alkoxycarbonyl having up to 6 carbon atoms,or by phenyl which is optionally substituted up to 5 times by identicalor different halogen atoms; or represents straight-chain or branchedalkenyl having up to 10 carbon atoms which is optionally substituted byhalogen, hydroxyl, carboxyl, straight-chain or branched alkoxycarbonylhaving up to 6 carbon atoms, or by phenyl which is optionallysubstituted up to 5 times by identical or different halogen atoms;ifappropriate in an isomeric form, or a physiologically acceptable saltthereof.